Bone morphogenetic proteins (BMPs) are a family of proteins which have been identified as having the ability to induce the formation of bone and cartilage in tissue extracts. BMPs are a subfamily within the TGF-.beta. superfamily. BMPs have multiple therapeutic uses, including a wide variety of settings where bone has been lost through physicological or traumatic processes.
The TGF-.beta. superfamily of proteins have been shown to bind to serine/threonine kinase receptors. Massague, Cell, 69:1067-1070 (1992); Attisano et al., Cell 68:97-108 (1992); Lin et al., Cell, 68:775-785 (1992); Wang et al., Cell 67:797-805 (1991). Similarly, activin receptors have been isolated and characterized as a predicted transmembrane serine kinase. Mathews et al., Cell 65:973-982 (1991); Nakamura et al., J. Biol. Chem. 267:18924-18,928 (1992). Ebner et al., Science, 260:1344-1348 (1993) describe the existence of Type I and Type II TGF-.beta. receptors, and the effects of the Type I receptor on binding of TGF-.beta. to the Type II receptor.
Type I receptor proteins have been reported not to bind to their ligand molecules independently, but, acting in concert with Type II receptor proteins, are observed to contribute to increased binding to the ligand. See Matsuzaki et al., J. Biol. Chem., 268:12719-12723 (1993); Ebner et al., Science, 260:1344-1348 (1993).
Paralkar et al., PNAS USA 88:3397-3401 (1991) describes the presence of high affinity binding sites for BPM-4 on MC3T3E1 and NIH3T3 cells. No competition by TGF-.beta. was found for the BMP-4 binding proteins, nor was competition by BPM-4 for TGF-.beta. receptors observed in Attisano et al., Cell 68:97-108 (1992).